Abstract
Vacuolar-ATPase (V-ATPase) has been proposed as a drug target in osteoporosis due to its involvement in bone resorption, and as a target in cancer due to potential involvement in tumor invasion and metastasis. The classical selective inhibitors of V-ATPase are microbial macrolides of the bafilomycin and concanamycin class. These inhibitors have proven to be too toxic for therapeutic use, however recent structure-activity studies on bafilomycins, and the isolation of novel macrolide structures from marine sources, have provided new avenues for development of potentially less toxic V-ATPase inhibitors. The novel salicylihalamide and lobatamide series of compounds were predicted to share a common mechanism of action based on the patterns of cytotoxicity produced in the NCI 60-cell cancer screen. They have subsequently been shown to selectively interact with mammalian V-ATPases, but not with fungal V-ATPases. With the recent achievement of total syntheses of salicylihalamide, lobatamide, and related compounds, the elaboration of congeners with specificity for particular enzyme isoforms may provide drug candidates which are less toxic. This review summarizes recent advances in V-ATPase inhibition and the prospects for further progress.
Keywords: v-atpase, salicylihalamides, lobatamides, inhibitors, cancer, osteoporosis, isolation, synthesis
Current Medicinal Chemistry
Title: Novel Marine and Microbial Natural Product Inhibitors of Vacuolar ATPase
Volume: 10 Issue: 9
Author(s): John A. Beutler and Tawnya C. McKee
Affiliation:
Keywords: v-atpase, salicylihalamides, lobatamides, inhibitors, cancer, osteoporosis, isolation, synthesis
Abstract: Vacuolar-ATPase (V-ATPase) has been proposed as a drug target in osteoporosis due to its involvement in bone resorption, and as a target in cancer due to potential involvement in tumor invasion and metastasis. The classical selective inhibitors of V-ATPase are microbial macrolides of the bafilomycin and concanamycin class. These inhibitors have proven to be too toxic for therapeutic use, however recent structure-activity studies on bafilomycins, and the isolation of novel macrolide structures from marine sources, have provided new avenues for development of potentially less toxic V-ATPase inhibitors. The novel salicylihalamide and lobatamide series of compounds were predicted to share a common mechanism of action based on the patterns of cytotoxicity produced in the NCI 60-cell cancer screen. They have subsequently been shown to selectively interact with mammalian V-ATPases, but not with fungal V-ATPases. With the recent achievement of total syntheses of salicylihalamide, lobatamide, and related compounds, the elaboration of congeners with specificity for particular enzyme isoforms may provide drug candidates which are less toxic. This review summarizes recent advances in V-ATPase inhibition and the prospects for further progress.
Export Options
About this article
Cite this article as:
Beutler A. John and McKee C. Tawnya, Novel Marine and Microbial Natural Product Inhibitors of Vacuolar ATPase, Current Medicinal Chemistry 2003; 10 (9) . https://dx.doi.org/10.2174/0929867033457827
DOI https://dx.doi.org/10.2174/0929867033457827 |
Print ISSN 0929-8673 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-533X |
Call for Papers in Thematic Issues
Advances in Medicinal Chemistry: From Cancer to Chronic Diseases.
The broad spectrum of the issue will provide a comprehensive overview of emerging trends, novel therapeutic interventions, and translational insights that impact modern medicine. The primary focus will be diseases of global concern, including cancer, chronic pain, metabolic disorders, and autoimmune conditions, providing a broad overview of the advancements in ...read more
Approaches to the treatment of chronic inflammation
Chronic inflammation is a hallmark of numerous diseases, significantly impacting global health. Although chronic inflammation is a hot topic, not much has been written about approaches to its treatment. This thematic issue aims to showcase the latest advancements in chronic inflammation treatment and foster discussion on future directions in this ...read more
Cellular and Molecular Mechanisms of Non-Infectious Inflammatory Diseases: Focus on Clinical Implications
The Special Issue covers the results of the studies on cellular and molecular mechanisms of non-infectious inflammatory diseases, in particular, autoimmune rheumatic diseases, atherosclerotic cardiovascular disease and other age-related disorders such as type II diabetes, cancer, neurodegenerative disorders, etc. Review and research articles as well as methodology papers that summarize ...read more
Chalcogen-modified nucleic acid analogues
Chalcogen-modified nucleosides, nucleotides and oligonucleotides have been of great interest to scientific research for many years. The replacement of oxygen in the nucleobase, sugar or phosphate backbone by chalcogen atoms (sulfur, selenium, tellurium) gives these biomolecules unique properties resulting from their altered physical and chemical properties. The continuing interest in ...read more
- Author Guidelines
- Graphical Abstracts
- Fabricating and Stating False Information
- Research Misconduct
- Post Publication Discussions and Corrections
- Publishing Ethics and Rectitude
- Increase Visibility of Your Article
- Archiving Policies
- Peer Review Workflow
- Order Your Article Before Print
- Promote Your Article
- Manuscript Transfer Facility
- Editorial Policies
- Allegations from Whistleblowers
- Announcements
Related Articles
-
The Safety of Bisphosphonate Use in Premenopausal Women on Corticosteroids
Current Drug Safety Receptor Mediated Tumor Targeting: An Emerging Approach for Cancer Therapy
Current Drug Delivery Flavonoids as Anticancer Agents: Recent Progress and State of the Art?
Current Organic Chemistry The Caveolin-1 Connection to Cell Death and Survival
Current Molecular Medicine Design, Synthesis and Cytotoxicity of Chalcone Analogs Derived from 2-Phenylimino-3-phenylthiazolidin-4-one
Letters in Drug Design & Discovery Rational Targeting of Peroxisome Proliferating Activated Receptor Subtypes
Current Medicinal Chemistry A Review of Pharmacological Treatment Options for Lung Cancer: Emphasis on Novel Nanotherapeutics and Associated Toxicity
Current Drug Targets Psoriasis and Vascular Risk : An Update
Current Pharmaceutical Design Immunomodulatory Effects of <i>Allium sativum</i> L. and its Constituents against Viral Infections and Metabolic Diseases
Current Topics in Medicinal Chemistry The Antitumoral Mode of Action of Imiquimod and Other Imidazoquinolines
Current Medicinal Chemistry Time Dependent Distribution of MicroRNA 144 after Intravenous Delivery
MicroRNA Photodynamic Therapy For Non-Melanoma Skin Cancers
Current Cancer Therapy Reviews Tyrosine Kinases as Therapeutic Targets in BCR-ABL Negative Chronic Myeloproliferative Disorders
Current Drug Targets Reversal of Bone Cancer Pain by HSV-1-Mediated Silencing of CNTF in an Afferent Area of the Spinal Cord Associated with AKT-ERK Signal Inhibition
Current Gene Therapy Anti-Cancer
Current Bioactive Compounds Folate Receptor Targeted Liposomes Encapsulating Anti-Cancer Drugs
Current Pharmaceutical Biotechnology The Clinical Significance of Incidental Parotid Uptake in a PET/CT Study: A Diagnostic Algorithm
Current Medical Imaging Radiolabeled Iron Oxide Nanoparticles As Dual-Modality SPECT/MRI and PET/MRI Agents
Current Topics in Medicinal Chemistry Antiangiogenesis in Myelodysplastic Syndrome
Current Cancer Drug Targets The Exploitation of Toll-like Receptor 3 Signaling in Cancer Therapy
Current Pharmaceutical Design